Pharmaceutical compounds

ABSTRACT

Pyrimidines of formula (I): 
                         
wherein R 1  to R 4 , X and Y are defined in the specification are inhibitors of P13K and may thus be used to treat diseases and disorders arising from abnormal cell growth, function or behavior associated with P13 kinase such as cancer, immune disorders, cardiovascular disease, viral infection, inflammation, metabolism/endocrine function disorders and neurological disorders.

This application is the U.S. national phase of International ApplicationNo. PCT/GB2006/003782, filed 11 Oct. 2006, which designated the U.S. andclaims priority to GB 0520657.8, filed 11 Oct. 2005, the entire contentsof each of which are hereby incorporated by reference.

FIELD OF THE INVENTION

The present invention relates to pyrimidine compounds and to their useas inhibitors of phosphatidylinositol 3-kinase (PI3K).

BACKGROUND TO THE INVENTION

Phosphatidylinositol (hereinafter abbreviated as “PI”) is one of anumber of phospholipids found in cell membranes. In recent years it hasbecome clear that PI plays an important role in intracellular signaltransduction. In the late 1980s, a PI3 kinase (PI3K) was found to be anenzyme which phosphorylates the 3-position of the inositol ring ofphosphatidylinositol (M. Whitman et al, 1988, Nature, 332, 644-646).

PI3K was originally considered to be a single enzyme, but it has nowbeen clarified that a plurality of subtypes are present in PI3K. Eachsubtype has its own mechanism for regulating activity. Three majorclasses of PI3Ks have been identified on the basis of their in vitrosubstrate specificity (B. Vanhaesebroeck et al, 1997, Trends inBiochemical Sciences, 22, 267-262). Substrates for class I PI3Ks are PI,PI 4-phosphate (PI4P) and PI 4,5-biphosphate (PI (4,5)P2). Class I PI3Ksare further divided into two groups, class Ia and class Ib, in terms oftheir activation mechanism. Class Ia PI3Ks include PI3K p110α, p110β andp110δ subtypes, which transmit signals from tyrosine kinase-coupledreceptors. Class Ib PI3K includes a p110γ subtype activated by a Gprotein-coupled receptor. PI and PI(4)P are known as substrates forclass II PI3Ks. Class II PI3Ks include PI3K C2α, C2β and C2γ subtypes,which are characterized by containing C2 domains at the C terminus. Thesubstrate for class III PI3Ks is PI only.

In the PI3K subtypes, the class Ia subtype has been most extensivelyinvestigated to date. The three subtypes of class Ia are heterodimers ofa catalytic 110 kDa subunit and regulatory subunits of 85 kDa or 55 kDa.The regulatory subunits contain SH2 domains and bind to tyrosineresidues phosphorylated by growth factor receptors with a tyrosinekinase activity or oncogene products, thereby inducing the PI3K activityof the p110 catalytic subunit which phosphorylates its lipid substrate.Thus, the class Ia subtypes are considered to be associated with cellproliferation and carcinogenesis.

WO 01/083456 describes a series of condensed heteroaryl derivativeswhich have activity as inhibitors of PI3 K and which suppress cancercell growth.

SUMMARY OF THE INVENTION

It has now been found that a series of novel pyrimidine compounds haveactivity as inhibitors of PI3K. The compounds exhibit selectivity forclass Ia PI3Ks over class Ib, in particular for the p110δ subtype.Accordingly, the present invention provides a compound which is apyrimidine of formula (I):

wherein

—XR³ is bonded at ring position 2 and —YR⁴ is bonded at ring position 5or 6, or —YR⁴ is bonded at ring position 2 and —XR³ is bonded at ringposition 6;

R¹ and R² form, together with the N atom to which they are attached, amorpholine ring which is unsubstituted or substituted;

X is selected from a direct bond, —O—, —CR′R″— and —NR′— wherein R′ andR″ are each, independently, H or C₁-C₆ alkyl;

R³ is an indole group which is unsubstituted or substituted; and either:

(a) Y is selected from —O—(CH₂)_(n)—, —NH—(CH₂)_(n)—, —NHC(O)—(CH₂)_(n)—and —C(O)NH—(CH₂)_(n)— wherein n is 0 or an integer of 1 to 3, and R⁴ isselected from an unsaturated 5- to 12-membered carbocyclic orheterocyclic group which is unsubstituted or substituted and a group—NR⁵R⁶ wherein R⁵ and R⁶, which are the same or different, are eachindependently selected from H, C₁-C₆ alkyl which is unsubstituted orsubstituted, C₃-C₁₀ cycloalkyl which is unsubstituted or substituted,—C(O)R, —C(O)N(R)₂ and —S(O)_(m)R wherein R and m are as defined above,or R⁵ and R⁶ together form, with the nitrogen atom to which they areattached, a saturated 5-, 6- or 7-membered N-containing heterocyclicgroup which is unsubstituted or substituted;

(b) Y is a direct bond and R⁴ is selected from an unsaturated 5- to12-membered carbocyclic or heterocyclic group which is unsubstituted orsubstituted, and a group —NR⁵R⁶ wherein R⁵ and R⁶, which are the same ordifferent, are each independently selected from H, C₁-C₆ alkyl which isunsubstituted or substituted, C₃-C₁₀ cycloalkyl which is unsubstitutedor substituted, —C(O)R, —C(O)N(R)₂ and —S(O)_(m)R wherein R and m are asdefined above;

or a pharmaceutically acceptable salt thereof.

The invention also provides a compound which is a pyrimidine of formula(I′):

wherein

-   P —XR³ is bonded at ring position 2 and —YR⁴ is bonded at ring    position 5 or 6, or —YR⁴ is bonded at ring position 2 and —XR³ is    bonded at ring position 6;-   R¹ and R², which are the same or different, are each independently    selected from H, C₁-C₆ alkyl which is unsubstituted or substituted,    C₃-C₁₀ cycloalkyl which is unsubstituted or substituted, and C₁-C₆    alkoxy which is unsubstituted or substituted, or R¹ and R² form,    together with the N atom to which they are attached, a saturated 5-,    6- or 7-membered N-containing heterocyclic ring which includes 0, 1    or 2 additional heteroatoms selected from O, N and S and which is    unsubstituted or substituted;-   X is selected from a direct bond, —O—, —CR′R″— and —NR′— wherein R′    and R″ are each, independently, H or C₁-C₆ alkyl;-   R³ is selected from:

(i) a group of the following formula:

wherein B is a phenyl ring which is unsubstituted or substituted and Zis selected from H, —OR, —SR, CH₂OR, —CO₂R, CF₂OH, CH(CF₃)OH, C(CF₃)₂OH,—(CH₂)_(q)OR, —(CH₂)_(q)NR₂, —C(O)N(R)₂, —NR₂, —NRC(O)R, —S(O)_(m)N(R)₂,—OC(O)R, OC(O)N(R)₂, —NRS(O)_(m)R, —NRC(O)N(R)₂, CN, halogen and —NO₂,wherein each R is independently selected from H, C₁-C₆ alkyl, C₃-C₁₀cycloalkyl and a 5- to 12-membered aryl or heteroaryl group, the groupbeing unsubstituted or substituted, m is 1 or 2 and q is 0, 1 or 2;

(ii) a heteroaryl group which contains 1, 2, 3 or 4 ring nitrogen atomsand 0, 1 or 2 additional heteroatoms selected from O and S, which groupis monocyclic or bicyclic and which is unsubstituted or substituted; and

(iii) a group comprising a benzene ring which is unsubstituted orsubstituted and which is fused to a heteroaryl group as defined above;and either:

(a) Y is selected from —O—(CH₂)_(n)—, —NH—(CH₂)_(n)—, —NHC(O)—(CH₂)_(n)—and —C(O)NH—(CH₂)_(n)— wherein n is 0 or an integer of 1 to 3, and R⁴ isselected from an unsaturated 5- to 12-membered carbocyclic orheterocyclic group which is unsubstituted or substituted and a group—NR⁵R⁶ wherein R⁵ and R⁶, which are the same or different, are eachindependently selected from H, C₁-C₆ alkyl which is unsubstituted orsubstituted, C₃-C₁₀ cycloalkyl which is unsubstituted or substituted,—C(O)R, —C(O)N(R)₂ and —S(O)_(m)R wherein R and m are as defined above,or R⁵ and R⁶ together form, with the nitrogen atom to which they areattached, a saturated 5-, 6- or 7-membered N-containing heterocyclicgroup which is unsubstituted or substituted;

(b) Y is a direct bond and R⁴ is selected from an unsaturated 5- to12-membered carbocyclic or heterocyclic group which is unsubstituted orsubstituted, and a group —NR⁵R⁶ wherein R⁵ and R⁶, which are the same ordifferent, are each independently selected from H, C₁-C₆ alkyl which isunsubstituted or substituted, C₃-C₁₀ cycloalkyl which is unsubstitutedor substituted, —C(O)R, —C(O)N(R)₂ and —S(O)_(m)R wherein R and m are asdefined above;

or a pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION OF THE INVENTION

A C₁-C₆ alkyl group is linear or branched. A C₁-C₆ alkyl group istypically a C₁-C₄ alkyl group, for example a methyl, ethyl, propyl,n-butyl, sec-butyl or tert-butyl group. A C₁-C₆ alkyl group isunsubstituted or substituted, typically by one or more groups Z asdefined above, or by one or more groups Z as defined above or R⁷ asdefined below. Typically it is C₁-C₄ alkyl, for example methyl, ethyl,i-propyl, n-propyl, t-butyl, s-butyl or n-butyl.

R⁷ is selected from C₁-C₆ alkoxy, OR⁸, SR⁸, S(O)_(m)R⁸, nitro, CN,halogen, —C(O)R⁸, —CO₂R⁸, —C(O)N(R⁸)₂ and —N(R⁸)₂, wherein each R⁸,which are the same or different when more than one is present in a givensubstituent, is selected from H, C₁-C₆ alkyl and C₃-C₁₀ cycloalkyl., andm is 1 or 2.

A halogen is F, Cl, Br or I. Preferably it is F, Cl or Br. A C₁-C₆ alkylgroup substituted by halogen may be denoted by the term “halo-C₁-C₆alkyl”, which means an alkyl group in which one or more hydrogens isreplaced by halo. A halo-C₁-C₆ alkyl group preferably contains one, twoor three halo groups. A preferred example of such a group istrifluoromethyl.

A C₁-C₆ alkoxy group is linear or branched. It is typically a C₁-C₄alkoxy group, for example a methoxy, ethoxy, propoxy, i-propoxy,n-propoxy, n-butoxy, sec-butoxy or tert-butoxy group. A C₁-C₆ alkoxygroup is unsubstituted or substituted, typically by one or more groups Zor R⁷ as defined above.

A C₃-C₁₀ cycloalkyl group may be, for instance, C₃-C₈ cycloalkyl such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.Typically it is C₃-C₆ cycloalkyl. A C₃-C₁₀ cycloalkyl group isunsubstituted or substituted, typically by one or more groups Z or R⁷ asdefined above.

A C₁-C₆ acyl group is a group —C(O)Alk in which Alk is C₁-C₆ alkyl asdefined above. It is, for instance, formyl, acetyl or propionyl.

A saturated 5-, 6-, or 7-membered N-containing heterocyclic ring may be,for example, piperidine, piperazine, morpholine or pyrrolidine. The ringtypically contains one nitrogen atom and either an additional N atom oran O atom, or no additional heteroatoms. The ring is unsubstituted orsubstituted on one or more ring carbon atoms and/or on any additional Natom present in the ring. Examples of suitable substituents include oneor more groups Z or R⁷ as defined above, and a C₁-C₆ alkyl group whichis unsubstituted or substituted by a group Z or R⁷ as defined above.When the ring is piperazine it is typically unsubstituted orsubstituted, typically on the second ring nitrogen atom, by —C(O)R⁸,—C(O)N(R⁸)₂ or —S(O)_(m)R⁸, or by C₁-C₆ alkyl which is unsubstituted orsubstituted by C₁-C₆ alkoxy or OH.

An unsaturated 5- to 12-membered carbocyclic group is a 5-, 6-, 7-, 8-,9-, 10, 11- or 12-membered carbocyclic ring containing at least oneunsaturated bond. It is a monocyclic or fused bicyclic ring system. Thegroup is aromatic or non-aromatic, for instance a 5- to 12-membered arylgroup. Examples include phenyl, naphthyl, indanyl, indenyl andtetrahydronaphthyl groups. The group is unsubstituted or substituted,typically by one or more groups Z or R⁷ as defined above.

An aryl group is a 5- to 12-membered aromatic carbocyclic group. It ismonocyclic or bicyclic. Examples include phenyl and naphthyl groups. Thegroup is unsubstituted or substituted, for instance by a group Z or R⁷as defined above.

An unsaturated 5- to 12-membered heterocyclic group is typicallyheteroaryl. Heteroaryl is a 5- to 12-membered heteroaryl group whichcontains 1, 2, 3, or 4 heteroatoms selected from O, N and S. Typicallyit contains one N atom and 0, 1, 2 or 3 additional heteroatoms selectedfrom O, S and N. It may be, for example, furan, thiophene, pyrrole,indole, isoindole, pyrazole, imidazole, benzothiophene, benzothiazole,benzofuran, isoxazole, oxazole, oxadiazole, thiazole, isothiazole,thiadiazole, dihydroimidizole, pyridine, pyridine, quinoline,isoquinoline, quinoxaline, thianopyrazine, pyran, pyrimidine,pyridazine, pyrazine, triazine, triazole or tetrazole. The group isunsubstituted or substituted, typically by one or more groups Z or R⁷ asdefined above. In the definition of R⁴ this heterocyclic group istypically selected from pyridine, thiophene and pyrrole. Most typicallyit is pyridine, for instance a pyrid-2-yl, pyrid-3-yl or pyrid-4-ylgroup.

In formula (I′) R¹ and R² typically form, together with the N atom towhich they are attached, a secondary or tertiary amine, most typically atertiary amine. The amine is acyclic or cyclic. Thus, one or both of R¹and R² is typically a C₁-C₆ alkyl group which is unsubstituted orsubstituted. If the alkyl group is substituted it is typicallysubstituted by Z or R⁷ as defined above. When R¹ or R² is a C₁-C₆ alkylgroup which is unsubstituted it is typically a methyl or ethyl group.When R¹ or R² is a C₁-C₆ alkyl group which is substituted it istypically C₁-C₆ alkyl substituted by a group selected from C₁-C₆ alkoxyand —NR₂ as defined above, for instance C₁-C₆ alkyl substituted by —OCH₃or by —NH₂, —NHCH₃ or —N(CH₃)₂. Thus one or both of R¹ and R² may be—(CH₂)_(r)—OR¹³ wherein r is 0 or an integer of 1 to 6, for instance 1to 4, such as 1, 2, 3 or 4, and R¹³ is C₁-C₆ alkyl. Alternatively one orboth of R¹ and R² may be —(CH₂)_(r)—NR₂ wherein r and R are as definedabove. Typically one or each of R¹ and R² is selected from —(CH₂)₂OCH₃,—(CH₂)₂NH₂, —(CH₂)₂NHCH₃ and —(CH₂)₂N(CH₃)₂.

In formula (I) R¹ and R² form, together with the N-atom to which theyare attached, a morpholine ring. The ring is unsubstituted orsubstituted, either on a ring carbon atom or (if present) on a secondheteroatom, for instance by a group Z or R⁷ as defined above.

In formula (I), in the definition of R³, the indole group is linked tothe pyrimidine ring via any available ring C or N atom. For instance, itis an indol-4-yl, indol-5-yl or indol-6-yl group. Typically it is anindol-4-yl or indol-6-yl group.

In formula (I′), in the definition (i) for R³, the phenyl ring B isunsubstituted (apart from group Z) or substituted. When it isunsubstituted the group Z is the sole substituent. When it issubstituted it typically comprises, in addition to group Z, one or moresubstituents selected from halo, alkyl, alkenyl, alkynyl, CN, NO₂, OR′,SR′, NR′₂, C(O)R′, SOR′, SO₂R′, SO₂NR′₂, NC(O)R′ and CO₂R′, wherein eachR′ is independently H or C₁-C₆ alkyl. Group Z is bonded to any availablering position on the phenyl ring B. Typically the phenyl ring, which isotherwise unsubstituted or substituted, for instance as specified above,is meta-substituted or para-substituted by Z. Thus it may be situated atthe 2-, 3-, 4-, 5- or 6- position of the phenyl ring.

Typically it is bonded at position 3 or 4. Z is most typically otherthan H, such that moiety -BZ is a substituted phenyl ring. A typicalexample of Z is a group OR as defined above, in particular OH. In thisembodiment the OR group, or OH group, is typically bonded at ringposition 3 or 4 of phenyl ring B. Typically -BZ is a 3-hydroxyphenyl or4-hydroxyphenyl group, or an isostere thereof.

An isostere as used herein is a functional group which possesses bindingproperties which are the same as, or similar to, the 3-hydroxyphenyl or4-hydroxyphenyl group in the context of the structure of formula (I). Anindole group is an isostere of 3-hydroxyphenyl and 4-hydroxyphenylgroups. In the definition for R³ in formula (I) the indole group isunsubstituted or substituted. If it is substituted it may be substitutedby one or more substituents selected from a group Z or R⁷ as definedabove, any group specified above as an additional substituent on thephenyl ring B, and an oxo group (═O). Typically, if substituted, theheteroaryl group is substituted by OH, NH₂ or an oxo group. In oneembodiment the heteroaryl group is unsubstituted.

In formula (I′), in definition (iii) for R³, the benzene ring isunsubstituted or substituted. If it is substituted it may be substitutedby a group Z or R⁷ as defined above or by any of the groups specifiedabove as options an additional substituent on the phenyl ring B. Theheteroaryl group to which the benzene ring is fused is itselfunsubstituted or substituted, for instance by a group Z or R⁷ as definedabove, by any group specified above as an option for an additionalsubstituent on the phenyl ring B, or by an oxo group (═O). In oneembodiment both the benzene ring and the heteroaryl group areunsubstituted.

Examples of the groups included in definitions (ii) and (iii) for R³ informula (I) include pyrrole, pyrazole, triazole, tetrazole, indazole,thiazole, isothiazole, oxazole, isoxazole, indole, isoindole,1,3-dihydro-indol-2-one, pyridine-2-one, pyridine, pyridin-3-ol,imidazole, 1,3-dihydro-benzimidazolone, benzimidazole, benzothiazole,benzothiadiazole, quinoline, isoquinoline, quinoxaline,pyrazolopyridine, aminopyrazolinone, imidazopyridine, pyrimidine,pyridazine, pyrazine and isatin groups. Preferred examples includeindazole, indole, pyrazole and tetrazole groups. These groups may beunsubstituted or substituted, for instance as specified above.

When R⁴ is an unsaturated 5- to 12-membered carbocyclic group it istypically an aromatic carbocyclic group such as phenyl or naphthyl. WhenR⁴ is an unsaturated 5- to 12-membered heterocyclic group it istypically pyridyl, for instance a pyrid-2-yl, pyrid-3-yl or pyrid-4-ylgroup. When R⁴ is a saturated 5-, 6- or 7- membered N-containingheterocyclic group it is typically a 6-membered such heterocyclic group,for instance piperidyl or morpholinyl. The group R⁴ is unsubstituted orsubstituted, for instance by a group Z or R⁷ as defined above.

The linker group X in formula (I) is typically a direct bond, —O—,—CH₂—, —CHR¹³—, —NH— or —NR¹³ wherein R¹³ is C₁-C₆ alkyl. Most typicallyit is a direct bond.

In one embodiment the pyrimidine is of formula (Ia):

wherein R¹, R², R³, R⁴, X and Y are as defined above for formula (I).

In formula (Ia) Y is typically —NH—C(O)— or C(O)—NH—; R⁴ is typically anaromatic unsaturated 5- to 12-membered carbocyclic or heterocyclic groupwhich is unsubstituted or substituted, for instance a phenyl or pyridylgroup. The pyridyl group may be a pyrid-2-yl, pyrid-3-yl or pyrid-4-ylgroup. XR³ is an indole group. Typically XR³ is an indol-4-yl orindol-6-yl group, more typically an indol-4-yl group. R¹ and R² form,together with the N atom to which they are attached, a morpholino group.

In a second embodiment the pyrimidine is of formula (Ib):

wherein R¹, R², R³, R⁴, Y and X are as defined above for formula (I).

In formula (Ib), Y is typically a direct bond or a group —O—(CH₂)_(n)—in which n is 1 or 2 and R⁴ is an aromatic unsaturated 5- to 12-memberedcarbocyclic or heterocyclic group which is unsubstituted or substituted,for instance a phenyl or pyridyl group. The phenyl group isunsubstituted or substituted, for instance by a group Z or a group R⁷ asdefined above, for example by a halogen such as Cl or Br. The pyridylgroup is unsubstituted or substituted by a group Z or R⁷ as definedabove. Alternatively Y may be a group —NH—(CH₂)_(n)— in which n is 1 or2 and R⁴ may be an aromatic unsaturated 5- to 12-membered carbocyclic orheterocyclic group or a group —NR⁵R⁶ as defined above, for instance agroup —NR⁵R⁶ wherein R⁵ and R⁶ form, together with the nitrogen atom towhich they are attached, or a saturated 5-, 6- or 7-memberedN-containing heterocyclic group. Typically R⁴ is an unsubstitutedpyrid-2-yl, pyrid-3-yl or pyrid-4-yl group, or a piperidine ormorpholine group. R¹ and R² preferably form, together with the N atom towhich they are attached, a morpholino group.

In a third embodiment the pyrimidine is of formula (Ic):

wherein R¹, R², R³, R⁴, Y and X are as defined above for formula (I).

In formula (Ic), Y may be a group —NH—(CH₂)_(n)— in which n is 1 or 2and R⁴ may be an aromatic unsaturated 5- to 12-membered carbocyclic orheterocyclic group or a group —NR⁵R⁶ as defined above, for instance agroup —NR⁵R⁶ wherein R⁵ and R⁶ form, together with the N atom to whichthey are attached, a saturated 5-, 6- or 7-membered N-containingheterocyclic group such as a piperidine or morpholine group. TypicallyR⁴ is an unsubstituted pyrid-2-yl, pyrid-3-yl or pyrid-4-yl group, or apiperidine or morpholine group. Alternatively Y may be a group—O—(CH₂)_(n)— in which n is 1 or 2 and R⁴ may be an aromatic unsaturated5- to 12-membered carbocyclic or heterocyclic group which isunsubstituted or substituted, for instance an unsubstituted pyrid-2-yl,pyrid-3-yl or pyrid-4-yl group.

Specific examples of compounds of the invention include:

-   6-(indol-4-yl)-4-(morpholin-4-yl)-2-[(2-(pyridin-2-yl)ethylamino]pyrimidine;-   2-(indol-4-yl)-4-(morpholin-4-yl)-6-[(2-(pyridin-2-yl)ethylamino]pyrimidine;-   6-(indol-4-yl)-4-(morpholin-4-yl)-2-[(2-(pyridin-3-yl)ethylamino]pyrimidine;-   2-(indol-4-yl)-4-(morpholin-4-yl)-6-[(2-(pyridin-3-yl)ethylamino]pyrimidine;-   6-(indol-4-yl)-4-(morpholin-4-yl)-2-[(2-(pyridin-4-yl)ethylamino]pyrimidine;-   2-(indol-4-yl)-4-(morpholin-4-yl)-6-[(2-(pyridin-4-yl)ethylamino]pyrimidine;-   2-(indol-4-yl)-4-(morpholin-4-yl)-6-(pyridin-2-ylmethyloxy)pyrimidine;-   6-(indol-4-yl)-4-(morpholin-4-yl)-2-(pyridin-2-ylmethyloxy)pyrimidine;-   6-(indol-6-yl)-4-(morpholin-4-yl)-2-[(2-(pyridin-2-yl)ethylamino]pyrimidine;-   2-(indol-6-yl)-4-(morpholin-4-yl)-6-[(2-(pyridin-2-yl)ethylamino]pyrimidine;-   6-(indol-6-yl)-4-(morpholin-4-yl)-2-[(2-(pyridin-3-yl)ethylamino]pyrimidine;-   2-(indol-6-yl)-4-(morpholin-4-yl)-6-[(2-(pyridin-3-yl)ethylamino]pyrimidine;-   6-(indol-6-yl)-4-(morpholin-4-yl)-2-[(2-(pyridin-4-yl)ethylamino]pyrimidine;-   2-(indol-6-yl)-4-(morpholin-4-yl)-6-[(2-(pyridin-4-yl)ethylamino]pyrimidine;-   2-(indol-6-yl)-4-(morpholin-4-yl)-6-(pyridin-2-ylmethyloxy)pyrimidine;-   6-(indol-6-yl)-4-(morpholin-4-yl)-2-(pyridin-2-ylmethyloxy)pyrimidine.    and the pharmaceutically acceptable salts thereof.

Pyrimidines of formula (I) may be converted into pharmaceuticallyacceptable salts, and salts may be converted into the free compound, byconventional methods. Pharmaceutically acceptable salts include salts ofinorganic acids such as hydrochloric acid, hydrobromic acid and sulfuricacid, and salts of organic acids such as acetic acid, oxalic acid, malicacid, methanesulfonic acid, trifluoroacetic acid, benzoic acid, citricacid and tartaric acid. In the case of compounds of the inventionbearing a free carboxy substituent, the salts include both theabove-mentioned acid addition salts and the salts of sodium, potassium,calcium and ammonium. The latter are prepared by treating the freepyrimidine of formula (I), or the acid addition salt thereof, with thecorresponding metal base or ammonia.

The pyrimidines of formula (I) may be prepared by any suitable syntheticroute, for instance selected from those set out in any of schemes 1 to 8below.

In scheme 1, R¹, R², R³, R⁴, X and Y are as defined above for formula(I) and Hal is a halogen. Compounds of formula (Ia) may be prepared bythe Suzuki coupling of a compound of formula (2) with a boronic acidR⁴Y—B(OH)₂ (Y is a to direct bond) in the presence of Pd (0) and a base,for instance using the general procedure described in Reference Example15 which follows. A compound of formula (2) may be prepared by treatinga compound of formula (5) with a halogen (Cl₂, Br₂, I₂) or a source ofhalogen (N-chlorosuccinimide, N-bromosuccinimide or N-iodosuccinimide)in an inert solvent. A compound of formula (5) may be prepared from acompound of formula (6) by treatment with phosphorous oxychloride in thepresence of an N, N-dialkylaniline, followed by treatment with an amineof formula NHR¹R² in an inert solvent in the presence of a base. Acompound of formula (4) may be prepared by treating a compound offormula (6) with a halogen in the presence of an acid.

A compound of formula (I) may alternatively be prepared by treating acompound of formula (3) with phosphorous oxychloride in the presence ofan N, N-dialkylaniline, followed by treatment with an amine of formulaNHR¹R² in an inert solvent in the presence of a base. A compound offormula (3) may be prepared by the Suzuki coupling of a compound offormula (4) with a boronic acid of formula R⁴Y—B(OH)₂ (Y is a directbond) in the presence of Pd (0) and a base.

In scheme 2, R¹, R², R³, R⁴, X and Y are as defined above for formula(I). Compounds of formula (Ib) may be prepared by treating compounds offormula (7) with an amine of formula HNR¹R² in an inert solvent in thepresence of a base. Compounds of formula (7) may be prepared by treatingcompounds of formula (8) with phosphorous oxychloride in the presence ofan N, N-dialkylaniline. Compounds of formula (8) may be prepared byreacting together compounds of formula (9) and (10) in an inert solvent.

Compounds of formula (10) were prepared according to the method inTetrahedron, 1991, 47, 975. Compounds of formula (9) were preparedaccording to J. Med. Chem., 1995, 38, 2251.

In scheme 3, R¹, R², R³, R⁴, X and Y are as defined above for formula(I). Compounds of formula (I) may be prepared by the Suzuki coupling ofeither a compound of formula (12) with a boronic acid of formulaR³X—B(OH)₂, or a compound of formula (11) with a boronic acid of formulaR⁴Y—B(OH)₂, in the presence of Pd and a base. Compounds of formulae (11)and (12) may be prepared by the Suzuki coupling of a compound of formula(13) with, respectively, a boronic acid of formula R³X—B(OH)₂ or aboronic acid of formula R⁴Y—B(OH)₂, in each case in the presence of Pdand a base. A compound of formula (13) may be prepared by treating asolution of a compound of formula (14) with an amine of formula HNR¹R²in the presence of a base. The trihalopyrimidines of formula (14) areknown compounds and may be obtained commercially or synthesized by knownmethods.

When R³ in the end product is an indolyl group, the required indoleboronic acid of formula R³X—B(OH)₂ may be prepared by treating thecorresponding brominated indole group with an alkyl lithium basefollowed by quenching with a trialkylborate. Alternatively, indoleboronic acid compounds are commercially available.

In Scheme 4, R¹, R², R³, R⁴ and X are as defined above for formula (I).Treatment of (51) with either a boronic acid R⁴—B(OH)₂ (Y is a directbond), a suitable alcohol R⁴—OH(Y is —O—(CH₂)_(n)— wherein n is 0) or anamine R⁴—NH₂ (Y is —NH—(CH₂)_(n)— wherein n is 0) gives compounds offormula (1b). Compounds of formula (11) may be prepared by treatingcompounds of formula (52) with one molar equivalent of an amine offormula HNR¹R² in an inert solvent in the presence of a base. Compoundsof formula (52) may be prepared by treating compounds of formula (53)with phosphorous oxychloride in the presence of an N, N-dialkylaniline.Compounds of formula (53) may be prepared by reacting together compoundsof formula (9) and (54) in an inert solvent in the presence of a base.

In Scheme 5, R¹, R², R³, R⁴, Y and X are as defined above for formula(I), and Hal is a halogen. Compounds of formula (Ib) or (1c) may beprepared by Suzuki coupling of compounds of formula (15) or (16)respectively with a boronic acid R³X—B(OH)₂ in the presence of Pd (0)and a base, for instance using the general procedure described inReference Example 15. A compound of formula (15) may be prepared bytreatment of a compound of formula (19) with one molar equivalent of anamine of formula HNR¹R² in an inert solvent in the presence of a base atroom temperature. A compound of formula (16) may be obtained bytreatment of a compound of formula (18) with two molar equivalents of anamine of formula HNR¹R² in an inert solvent at elevated temperature (forexample 80° C.).

The isomeric compounds (18) and (19) can both be prepared by treating acompound of formula (20) with either a boronic acid R⁴—B(OH)₂ (Y is adirect bond), a suitable alcohol R⁴—OH(Y is —O—(CH₂)_(n)— wherein n is0) or an amine R⁴—NH₂ (Y is —NH—(CH₂)_(n)— wherein n is 0) andseparating the two products.

Alternatively a compound of formula (16) may be prepared by treatment ofa compound of formula (17) with either a boronic acid R⁴—B(OH)₂ (Y is adirect bond), a suitable alcohol R⁴—OH(Y is —O—(CH₂)_(n)— wherein n is0) or an amine R⁴—NH₂ (Y is —NH—(CH₂)_(n)— wherein n is 0). A compoundof formula (17) may be prepared by treatment of a compound of formula(20) with one molar equivalent of an amine of formula HNR¹R² in an inertsolvent in the presence of a base. Compounds of formulae (19) and (18)were prepared as described in Reference Example 3.

When R³ in the end product is an indolyl group, the required indoleboronic acid of formula R³X—B(OH)₂ may be prepared by treating thecorresponding brominated indole with an alkyl lithium base followed byquenching with a trialkylborate. Alternatively, an indole boronic acidmay be obtained commercially.

A compound (1b) or (1c) in which X is other than a direct bond may beprepared by treating the intermediate (16) or (15), respectively, with asuitable amine, alcohol or thiol nucleophile under neutral or basicconditions.

In Scheme 6, R¹, R², R⁴ and OR are as defined above for formula (I) ORbeing one option for R³ in formula (I)). Compounds of formula (Ia) canbe prepared by coupling of an acid of structure (21) with an amine byone of the standard methods of amide bond formation. Compounds like (21)can be obtained by hydrolysis of esters of type (22). Structures like(22) can be obtained from compounds of formula (23) by treatment withphosphorous oxychloride in the presence of an N, N-dialkylaniline,followed by treatment with an amine of formula NHR¹R² in an inertsolvent in the presence of a base. Compounds like (23) can be obtainedby reacting together compounds of formula (9a) with commerciallyavailable compound (24) in an inert solvent. Compounds (23), (22) and(21) can be prepared as described in Reference Examples 7 to 9 whichfollow.

An indole analogue of the end product of formula (Ia), in which theOR-substituted phenyl group is replaced by an indole group, may beprepared according to scheme 6 by replacing the amidine compound (9a) bya corresponding amidine in which the OR-substituted phenyl group isreplaced by an indole group. The amidine in this case may be prepared,for instance, by the addition of ammonia or a synthetic equivalentthereof to the corresponding indole nitrile, followed by acidic work up.

In scheme 7, R¹, R², R³ and X are as defined for formula (I) and Ar isan unsaturated 5- to 12-membered carbocyclic or heterocyclic group whichis unsubstituted or substituted, as defined above within the definitionof R⁴ in formula (I). Compounds of formula (I) can be prepared by thereaction of a compound of formula (25) with an acid chloride in thepresence of a base in an inert solvent. A compound of formula (25) canbe prepared by reduction of a compound of formula (26), using forexample catalytic hydrogenation over a suitable metal catalyst. Acompound of formula (26) may be prepared by Suzuki coupling of compoundsof formula (27) with a boronic acid R³X—B(OH)₂ in the presence of Pd (0)and a base. Compounds of formula (27) can be prepared by treatment ofcompound (28) with an amine of formula NHR¹R² in an inert solvent in thepresence of a base. Compound (28) can be prepared by treatment ofcommercially available 5-nitrouracil with phosphorous oxychloride in thepresence of an N, N-dialkylaniline.

In scheme 8, R¹, R², R³, R⁴, X and Y are as defined above for formula(I) and R⁶ is linear or branched C₁-C₄ alkyl or SiR⁷R⁸R⁹ wherein each ofR⁷, R⁸ and R⁹, which are the same or different, is linear or branchedC₁-C₄ alkyl, or phenyl. Compounds of formula (1a) may be prepared bySuzuki coupling of compounds of formula (29) with a boronic acidR³X—B(OH)₂ in the presence of Pd (0) and a base, for instance using thegeneral procedure described in Reference Example 15. A compound offormula (29) may be prepared by treatment of a compound of formula (30)with phosphorous oxychloride in the presence of an N, N-dialkylaniline,followed by treatment with an amine of formula NHR¹R² in an inertsolvent in the presence of a base. Compounds like (30) could be preparedby coupling of compounds of type (31) with for example a boronic acidR³X—B(OH)₂.

In scheme 9, R¹, R², R³, R⁴, X and Y are as defined above for formula(I). Compounds of formula 1a may be prepared by treatment of a compoundof formula 40 with a suitable reducing agent (eg. hydrogen). A compoundof formula 40 may be prepared by treatment of a compound of formula 41with an amine of formula NHR¹R² in an inert solvent in the presence of abase. A compound of formula 41 may be prepared from a compound offormula 42 by treatment with phosphorous oxychloride in the presence ofan N,N-dialkylaniline. Compounds of formula 42 may be prepared byreacting together compounds of formula 9 and 43 in an inert solvent inthe presence of a base. Compounds of formula 43 may be prepared fromcommercially available dimethyl halomalonate compounds (where halorefers to chloro, bromo or iodo) by means of suitable nucleophilicdisplacement reactions.

Compounds of the present invention have been found in biological teststo be inhibitors of PI3 kinase. The compounds are selective for class IaPI3 kinases over class Ib and typically exhibit at least a 20-foldselectivity for class Ia over class Ib PI3 kinases. In general thecompounds are selective for the p110δ isoform over p110γ.

A compound of the present invention may thus be used as an inhibitor ofPI3 kinase, in particular of a class Ia PI3 kinase. Accordingly, acompound of the present invention can be used to treat a disease ordisorder arising from abnormal cell growth, function or behaviourassociated with PI3 kinase. Examples of such diseases and disorders arediscussed by Drees et al in Expert Opin. Ther. Patents (2004) 14(5):703-732. These include proliferative disorders such as cancer, immunedisorders, cardiovascular disease, viral infection, inflammation,metabolism/endocrine disorders and neurological disorders. Examples ofmetabolism/endocrine disorders include diabetes and obesity. Examples ofcancers which the present compounds can be used to treat includeleukaemia, brain tumours, renal cancer, gastric cancer and cancer of theskin, bladder, breast, uterus, lung, colon, prostate, ovary andpancreas.

A compound of the present invention may be used as an inhibitor of PI3kinase. A human or animal patient suffering from a disease or disorderarising from abnormal cell growth, function or behaviour associated withPI3 kinase, such as an immune disorder, cancer, cardiovascular disease,viral infection, inflammation, a metabolism/endocrine disorder or aneurological disorder, may thus be treated by a method comprising theadministration thereto of a compound of the present invention as definedabove. The condition of the patient may thereby be improved orameliorated.

A compound of the present invention can be administered in a variety ofdosage forms, for example orally such as in the form of tablets,capsules, sugar- or film-coated tablets, liquid solutions or suspensionsor parenterally, for example intramuscularly, intravenously orsubcutaneously. The compound may therefore be given by injection orinfusion.

The dosage depends on a variety of factors including the age, weight andcondition of the patient and the route of administration. Daily dosagescan vary within wide limits and will be adjusted to the individualrequirements in each particular case. Typically, however, the dosageadopted for each route of administration when a compound is administeredalone to adult humans is 0.0001 to 50 mg/kg, most commonly in the rangeof 0.001 to 10 mg/kg, body weight, for instance 0.01 to 1 mg/kg. Such adosage may be given, for example, from 1 to 5 times daily. Forintravenous injection a suitable daily dose is from 0.0001 to 1 mg/kgbody weight, preferably from 0.0001 to 0.1 mg/kg body weight, A dailydosage can be administered as a single dosage or according to a divideddose schedule.

A compound of the invention is formulated for use as a pharmaceutical orveterinary composition also comprising a pharmaceutically orveterinarily acceptable carrier or diluent. The compositions aretypically prepared following conventional methods and are administeredin a pharmaceutically or veterinarily suitable form. The compound may beadministered in any conventional form, for instance as follows:

A) Orally, for example, as tablets, coated tablets, dragees, troches,lozenges, aqueous or oily suspensions, liquid solutions, dispersiblepowders or granules, emulsions, hard or soft capsules, or syrups orelixirs. Compositions intended for oral use may be prepared according toany method known in the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavouringagents, colouring agents and preserving agents in order to providepharmaceutically elegant and palatable preparations.

Tablets contain the active ingredient in admixture with non-toxicpharmaceutically acceptable excipients which are suitable for themanufacture of tablets. These excipients may be for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose,dextrose, saccharose, cellulose, corn starch, potato starch, calciumphosphate or sodium phosphate; granulating and disintegrating agents,for example, maize starch, alginic acid, alginates or sodium starchglycolate; binding agents, for example starch, gelatin or acacia;lubricating agents, for example silica, magnesium or calcium stearate,stearic acid or talc; effervescing mixtures; dyestuffs, sweeteners,wetting agents such as lecithin, polysorbates or lauryl sulphate. Thetablets may be uncoated or they may be coated by known techniques todelay disintegration and adsorption in the gastrointestinal tract andthereby provide a sustained action over a longer period. For example, atime delay material such as glyceryl monostearate or glyceryl distearatemay be employed. Such preparations may be manufactured in a knownmanner, for example by means of mixing, granulating, tableting, sugarcoating or film coating processes.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is present as such, ormixed with water or an oil medium, for example, peanut oil, liquidparaffin, or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example, sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose,sodium alginate, polyvinylpyrrolidone gum tragacanth and gum acacia;dispersing or wetting agents may be naturally-occurring phosphatides,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides for example polyoxyethylene sorbitan monooleate.

The said aqueous suspensions may also contain one or more preservatives,for example, ethyl or n-propyl p-hydroxybenzoate, one or more colouringagents, such as sucrose or saccharin.

Oily suspension may be formulated by suspending the active ingredient ina vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol.

Sweetening agents, such as those set forth above, and flavouring agentsmay be added to provide a palatable oral preparation. These compositionsmay be preserved by this addition of an antioxidant such as ascorbicacid. Dispersible powders and granules suitable for preparation of anaqueous suspension by the addition of water provide the activeingredient in admixture with a dispersing or wetting agent, a suspendingagent and one or more preservatives. Suitable dispersing or wettingagents and suspending agents are exemplified by those already mentionedabove. Additional excipients, for example sweetening, flavouring andcolouring agents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oils, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally occurring phosphatides, for example soy bean lecithin, andesters or partial esters derived from fatty acids an hexitol anhydrides,for example sorbitan mono-oleate, and condensation products of the saidpartial esters with ethylene oxide, for example polyoxyethylene sorbitanmonooleate. The emulsion may also contain sweetening and flavouringagents. Syrups and elixirs may be formulated with sweetening agents, forexample glycerol, sorbitol or sucrose. In particular a syrup fordiabetic patients can contain as carriers only products, for examplesorbitol, which do not metabolize to glucose or which only metabolize avery small amount to glucose.

Such formulations may also contain a demulcent, a preservative andflavouring and coloring agents;

B) Parenterally, either subcutaneously, or intravenously, orintramuscularly, or intrasternally, or by infusion techniques, in theform of sterile injectable aqueous or oleaginous suspensions. Thissuspension may be formulated according to the known art using thosesuitable dispersing of wetting agents and suspending agents which havebeen mentioned above. The sterile injectable preparation may also be asterile injectable solution or suspension in a non-toxicpaternally-acceptable diluent or solvent, for example as a solution in1,3-butane diol.

Among the acceptable vehicles and solvents that may be employed arewater, Ringer's solution and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil may beemployed including synthetic mono- or diglycerides. In addition fattyacids such as oleic acid find use in the preparation of injectables;

C) By inhalation, in the form of aerosols or solutions for nebulizers;

D) Rectally, in the form of suppositories prepared by mixing the drugwith a suitable non-irritating excipient which is solid at ordinarytemperature but liquid at the rectal temperature and will therefore meltin the rectum to release the drug. Such materials are cocoa butter andpoly-ethylene glycols;

E) Topically, in the form of creams, ointments, jellies, collyriums,solutions or suspensions.

The invention will be further described in the Examples which follow:

REFERENCE EXAMPLE 1 Preparation of Intermediates (18) and (19) in Scheme5 2,4-dichloro-6-(pyridin-2-ylmethylamino)pyrimidine (L1) and4,6-dichloro-2-(pyridin-2-ylmethylamino)pyrimidine (M1)

A solution of 2,4,6-trichloropyrimidine (1.00 g, 5.45 mmol) in dioxane(15 ml) at room temperature was treated with diisopropylethylamine (1.1eq, 6.00 mmol, 1.04 ml) and dropwise with 2-aminomethylpyridine (1.1 eq,6.00 mmol, 0.62 ml) and stirred for 2 h. tlc analysis (EtOAc-hexane,3:1) showed conversion to 2 products. The dioxane was evaporated invacuo, and the residue partitioned between H₂O (15 ml) and CHCl₃ (15ml). The organic layer was separated and the aqueous layer furtherextracted with CHCl₃ (2×10 ml). The combined extracts were dried(Na₂SO₄) and concentrated in vacuo. Purification by columnchromatography (same eluent) gave the product L1 (575 mg, 41%) and the2-isomer M1 (280 mg, 20%) as pale yellow solids.

-   L1: δ_(H) (250 MHz, CDCl₃) 8.49 (1H, d, J 4.5, pyridine Ar), 7.66    (1H, td, J 7.5, 1.5, pyridine Ar), 7.25-7.17 (2H, m, 2× pyridine    Ar), 6.85 (1H, br, NH), 6.36 (1H, s, br, pyrimidine Ar), 4.66 (2H,    br, CH₂).-   M1: δ_(H) (250 MHz, CDCl₃) 8.49 (1H, d, J 4.5, pyridine Ar), 7.61    (1H, td, J 7.5, 1.5, pyridine Ar), 7.24-7.12 (2H, m, 2× pyridine    Ar), 6.71 (1H, br, NH), 6.56 (1H, s, pyrimidine Ar), 4.66 (2H, d, J    5.0, CH₂).

Examples of further compounds of formula (18) that were prepared usingthis method are as follows:

2,4-dichloro-6-(pyridin-3-ylmethylamino)pyrimidine (N1)

δ_(H) (250 MHz, CDCl₃) 8.50 (2H, m, 2× pyridine Ar), 7.62 (1H, d, J 7.5,pyridine Ar), 7.28-7.25 (1H, m, pyridine Ar), 6.26 (1H, s, pyrimidineAr), 5.95 (1H, br, NH), 4.58 (2H, br, CH₂).

2,4-dichloro-6-[(2-(pyridin-2-yl)ethylamino]pyrimidine (O1)

δ_(H) (250 MHz, CDCl₃) 8.55 (1H, d, J 4.0, pyridine Ar), 7.66 (1H, td, J7.5, 2.0, pyridine Ar), 7.23-7.19 (2H, m, 2× pyridine Ar), 6.66 (1H, br,NH), 6.31 (1H, s, pyrimidine Ar), 3.92-3.85 (2H, m, NHCH₂), 3.12 (2H, t,16.0, ArCH₂).

2,4-dichloro-6-[2-(pyridin-3-yl)ethylamino]pyrimidine (P1)

δ_(H) (250 MHz, CDCl₃) 8.41-8.37 (1H, m, pyridine Ar), 7.48 (2H, d, J8.0, pyridine Ar), 7.20 (1H, t, J 6.0, pyridine Ar), 6.20 (1H, s,pyrimidine Ar), 5.75 (1H, br, NH), 3.63-3.61 (2H, m, NHCH₂), 2.88 (2H,t, J 7.0, ArCH₂).

2,4-dichloro-6-[2-(pyridin-4-yl)ethylamino]pyrimidine (Q1)

δ_(H) (250 MHz, CDCl₃) 8.47 (2H, d, J 6.0, 2× pyridine Ar), 7.08 (2H, d,J 6.0, 2× pyridine Ar), 6.20 (1H, s, pyrimidine Ar), 5.28 (1H, br, NH),3.62 (2H, s, br, NHCH₂), 2.87 (2H, t, J 7.0, ArCH₂).

2,4-dichloro-6-[2-(morpholin-4-yl)ethylamino]pyrimidine (R1)

δ_(H) (250 MHz, CDCl₃) 6.21 (1H, br s, pyrimidine Ar), 5.97 (1H, br,NH), 3.63-3.60 (4H, m, 2× morpholine CH₂), 3.41-3.31 (2H, m, br, NHCH₂),2.51 (2H, t, J 6.0, ArCH₂), 2.40-2.37 (4H, m, 2× morpholine CH₂).

2,4-dichloro-6-[2-piperidin-1-yl)ethylamino]pyrimidine (S1)

δ_(H) (250 MHz, CDCl₃) 6.21 (1H, br s, pyrimidine Ar), 6.05 (1H, br, NH,3.39 (1H, br, q, J 5.0, NHCH_(A)H_(B)), 3.15 (1H, br, NHCH_(A)H_(B)),2.47 (2H, t, J 6.0, NCH₂), 2.32-2.30 (4H, br, 2× piperidine CH₂),1.55-1.48 (4H, m, 2× piperidine CH₂), 1.40-1.38 (2H, m, piperidine CH₂).

Examples of compounds of formula (19) that were prepared using thismethod are as follows:

4,6-dichloro-2-(pyridin-3-ylmethylamino)pyrimidine (T1)

δ_(H) (250 MHz, CDCl₃) 8.55 (1H, d, J 2.0, pyridine Ar), 8.47 (1H, dd, J5.0, 1.5, pyridine Ar), 7.61 (1H, dd, J 8.0, 2.0, pyridine Ar),7.24-7.20 (1H, m, pyridine Ar), 6.59 (1H, s, pyrimidine Ar), 6.06 (1H,br, NH), 4.59 (2H, d, J 6.0, CH₂).

4,6-dichloro-2-(pyridin-4-ylmethylamino)pyrimidine (U1)

δ_(H) (250 MHz, CDCl₃) 8.49 (2H, d, J 6.0, 2× pyridine Ar), 7.17 (2H, d,J 6.0, 2× pyridine Ar), 6.60 (1H, s, pyrimidine Ar), 6.24 (1H, br, NH),4.61 (2H, d, J 6.5, CH₂).

4,6-dichloro-2-[(2-(pyridin-2-yl)ethylamino]pyrimidine (V1)

δ_(H) (250 MHz, CDCl₃) 8.48 (1H, d, J 6.0, pyridine Ar), 7.54 (1H, td, J7.5, 2.0, pyridine Ar), 7.11-7.06 (2H, m, 2× pyridine Ar), 6.50 (1H, s,pyrimidine Ar), 6.20 (1H, br, NH), 3.80 (2H, q, J 6.0, NHCH₂), 3.01 (2H,t, J 6.0, ArCH₂).

4,6-dichloro-2-[2-(pyridin-3-yl)ethylamino]pyrimidine (W1)

δ_(H) (250 MHz, CDCl₃) 8.43 (2H, m, 2× pyridine Ar), 7.50 (1H, dt, J7.5, 2.0, pyridine Ar), 7.21-7.16 (1H, m, pyridine Ar), 6.55 (1H, s,pyrimidine Ar), 5.48 (1H, br, NH), 3.64 (2H, q, J 7.0, NHCH₂), 2.85 (2H,q, J 7.0, ArCH₂).

4,6-dichloro-2-[2-(pyridin-4-yl)ethylamino]pyrimidine (X1)

δ_(H) (250 MHz, CDCl₃) 8.46 (2H, dd, J 4.5, 1.5, 2× pyridine Ar), 7.09(2H, dd, J 4.5, 1.5, 2× pyridine Ar), 6.55 (1H, s, pyrimidine Ar), 5.54(1H, br, NH), 3.66 (2H, q, J 7.0, NHCH₂), 2.84 (2H, t, J 7.0, ArCH₂).

4,6-dichloro-2-[2-(morpholin-4-yl)ethylamino]pyrimidine (Y1)

δ_(H) (250 MHz, CDCl₃) 6.52 (1H, s, pyrimidine Ar), 6.00 (1H, br, NH),3.66-3.62 (4H, m, 2× morpholine CH₂), 3.43 (2H, q, J 6.0, NHCH₂), 2.50(2H, t, J 6.0, NCH₂), 2.43-2.39 (4H, m, 2× morpholine CH₂).

4,6-dichloro-2-[2-piperidin-1-yl)ethylamino]pyrimidine (Z1)

δ_(H) (250 MHz, CDCl₃) 6.50 (1H, s, pyrimidine Ar), 6.12 (1H, br, NH),3.40 (2H, q, J 5.5, NHCH₂), 2.44 (2H, t, J 6.0, NCH₂), 2.33-2.31 (4H, m,2× piperidine CH₂), 1.54-1.46 (4H, m, 2× piperidine CH₂), 1.41-1.37 (2H,m, 1× piperidine CH₂).

REFERENCE EXAMPLE 2 Preparation of Further Intermediates (18) and (19)in Scheme 5 4,6-dichloro-2-(pyridin-2-ylmethyloxy)pyrimidine (A2) and2,4-dichloro-6-(pyridin-2-ylmethyloxy)pyrimidine (B2)

Compounds A2 and B2 were prepared according to the method described inWO 99/65881, as follows:

248 mg of NaH (60% in mineral oil, 10.36 mmol) was added to a solutionof 2-pyridinemethanol (0.90 eq, 9.81 mmol, 0.95 ml) in THF (20 ml) atroom temperature and stirred for 30 minutes. After cooling to −78° C.,2,4,6-trichloropyrimidine (2 g, 10.90 mmol) was added dropwise and thereaction allowed to warm to room temperature and stirred for 3 h.Saturated aqueous NH₄Cl (20 ml) was added and the mixture extracted withEtOAc (20 ml). The organic phase was dried (MgSO₄) and evaporated invacuo. Column chromatography (EtOAc-DCM, 1:1) gave a mixture of the twoproducts (491 mg, 18%) as a pale yellow solid and in a ratio of 2.4:1,with compound B2 tentatively assigned as the major isomer; δ_(H) (250MHz, CDCl₃) 8.66-8.61 (2H, m, 1× pyridine Ar major, 1× pyridine Arminor), 7.75 (1H, td, J 8.0, 2.0, 1× pyridine Ar major), 7.74 (1H, td, J8.0, 2.0, 1× pyridine Ar minor), 7.53 (1H, d, J 8.0, 1× pyridine Arminor), 7.44 (1H, d, J 8.0, 1× pyridine Ar major), 7.32-7.24 (1H, 2H, m,1× pyridine Ar major, 1× pyridine Ar minor), 7.09 (1H, s, pyrimidine Arminor), 6.84 (1H, s, pyrimidine Ar major), 5.59 (2H, s, CH₂ minor), 5.58(2H, s, CH₂ major).

REFERENCE EXAMPLE 3 Preparation of Intermediates (15) in Scheme 56-chloro-4-(morpholin-4-yl)-2-(pyridin-2-ylmethylamino)pyrimidine (C2)

A solution of compound M1 (100 mg, 0.39 mmol) in dioxane (1 ml) at roomtemperature was treated with diisopropylethylamine (1.5 eq, 0.59 mmol,0.10 ml) and morpholine (1.5 eq, 0.59 mmol, 0.05 ml) and stirred at roomtemperature for 2 h. tlc analysis (EtOAc) then showed completeconversion. The dioxane was evaporated in vacuo, and the residuepartitioned between H₂O (5 ml) and CHCl₃ (5 ml). The organic layer wasseparated and the aqueous layer further extracted with CHCl₃ (2×2 ml).The combined extracts were dried (Na₂SO₄) and concentrated in vacuo.Purification by column chromatography (same eluent) gave the product(101 mg, 83%) as a colourless solid; δ_(H) (250 MHz, CDCl₃) 8.47 (1H, d,J 4.0, pyridine Ar), 7.56 (1H, td, J 7.5, 2.0, pyridine Ar), 7.24-7.20(1H, m, pyridine Ar), 7.09 (1H, dd, J 7.5, 5.0, pyridine Ar), 6.07 (1H,br, NH), 5.81 (1H, s, pyrimidine Ar), 4.62 (2H, d, J 5.5, NHCH₂),3.67-3.60 (4H, m, 2× morpholine CH₂), 3.46-3.42 (4H, m, 2× morpholineCH₂).

Using an analogous method the following further compounds (15) wereprepared:

6-chloro-4-(morpholin-4-yl)-2-(pyridin-3-ylmethylamino)pyrimidine (D2)

δ_(H) (250 MHz, CDCl₃) 8.52 (1H, s, pyridine Ar), 8.43 (1H, d, J 4.0,pyridine Ar), 7.58 (1H, d, J 8.0, pyridine Ar), 7.18-7.15 (1H, m,pyridine Ar), 5.83 (1H, s, pyrimidine Ar), 5.61 (1H, br, NH), 4.52 (2H,d, J 6.0, NHCH₂), 3.65-3.62 (4H, m, 2× morpholine CH₂), 3.46-3.42 (4H,m, 2× morpholine CH₂).

6-chloro-4-(morpholin-4-yl)-2-(pyridin-4-ylmethylamino)pyrimidine (E2)

δ_(H) (250 MHz, CDCl₃) 8.50 (2H, d, J 6.0, 2× pyridine Ar), 7.32 (2H, d,J 6.0, 2× pyridine Ar), 5.86 (1H, s, pyrimidine Ar), 5.52 (1H, br, NH),4.57 (2H, d, J 6.0, NHCH₂), 3.64-3.60 (4H, m, 2× morpholine CH₂),3.43-3.39 (4H, m, 2× morpholine CH₂).

6-chloro-4-(morpholin-4-yl)-2-[(2-(pyridin-2-yl)ethylamino]pyrimidine(F2)

δ_(H) (250 MHz, CDCl₃) 8.47 (1H, d, J 5.0, pyridine Ar), 7.52 (1H, td, J7.5, 2.0, pyridine Ar), 7.09-7.04 (2H, m, 2× pyridine Ar), 5.77 (1H, s,pyrimidine Ar), 5.38 (1H, br t, J 5.0, NH), 3.78-3.65 (6H, m, 2×morpholine CH₂ and NHCH₂), 3.57-3.46 (4H, m, 2× morpholine CH₂), 2.98(2H, t, J 6.5, ArCH₂).

6-chloro-4-(morpholin-4-yl)-2-[(2-(pyridin-3-yl)ethylamino]pyrimidine(G2)

δ_(H) (250 MHz, CDCl₃) 8.41-8.38 (2H, m, pyridine Ar), 7.45 (1H, d, J7.5, pyridine Ar), 7.17-7.12 (1H, m, pyridine Ar), 5.80 (1H, s,pyrimidine Ar), 5.18 (1H, br, NH), 3.74-3.66 (4H, m, 2× morpholine CH₂),3.56 (2H, q, J 7.0, NHCH₂), 3.50-3.41 (4H, m, 2× morpholine CH₂), 2.82(2H, t, J 7.0, ArCH₂).

6-chloro-4-(morpholin-4-yl)-2-[(2-(pyridin-4-yl)ethylamino]pyrimidine(H2)

δ_(H) (250 MHz, CDCl₃) 8.45 (2H, d, J 6.0, 2× pyridine Ar), 7.11 (2H, d,J 6.0, 2× pyridine Ar), 5.82 (1H, s, pyrimidine Ar), 4.98 (1H, br, NH),3.70-3.66 (4H, m, 2× morpholine CH₂), 3.59 (2H, q, J 7.0, NHCH₂), 3.49(4H, m, 2× morpholine CH₂), 2.83 (2H, t, J 7.0, ArCH₂).

6-chloro-4-(morpholin-4-yl)-2-[2-(morpholin-4-yl)ethylamino]pyrimidine

δ_(H) (250 MHz, CDCl₃) 5.79 (1H, s, pyrimidine Ar), 5.45 (1H, br, NH),3.69-3.58 (8H, m, 4× morpholine CH₂), 3.51-3.47 (4H, m, 2× morpholineCH₂), 3.39 (2H, q, J 6.0, NHCH₂), 2.49 (2H, t, J 6.0, NCH₂), 2.44-2.40(4H, m, 2× morpholine CH₂).

6-chloro-4-(morpholin-4-yl)-2-(pyridin-2-ylmethyloxy)pyrimidine (J2)

δ_(H) (250 MHz, CDCl₃) 8.49 (1H, d, J 5.0, 1× pyridine Ar), 7.63 (1H,td, J 8.0, 2.0, 1× pyridine Ar), 7.44 (1H, d, J 8.0, 1× pyridine Ar),7.14 (1H, dd, J 8.0, 5.0, 1× pyridine Ar), 6.11 (1H, s, pyrimidine Ar),5.41 (2H, s, OCH₂), 3.68-3.64 (4H, m, 2× morpholine CH₂), 3.53-3.50 (4H,m, 2× morpholine CH₂).

REFERENCE EXAMPLE 4 Preparation of Intermediates (16) in Scheme 52-chloro-4-(morpholin-4-yl)-6-(pyridin-2-ylmethylamino)pyrimidine (K2)

A solution of compound L1 (100 mg, 0.39 mmol) in dioxane (1 ml) wastreated with diisopropylethylamine (1.5 eq, 0.59 mmol, 0.10 ml) andmorpholine (1.8 eq, 0.70 mmol, 0.06 ml) and heated to 70° C. for 8hours. tlc analysis (CHCl₃-MeOH, 9:1) showed complete conversion. Thedioxane was evaporated in vacuo, and the residue partitioned between H₂O(5 ml) and CHCl₃ (5 ml). The organic layer was separated and the aqueouslayer further extracted with CHCl₃ (2×2 ml). The combined extracts weredried (Na₂SO₄) and concentrated in vacuo. Purification by columnchromatography (same eluent) gave the product (91 mg, 76%) as acolourless solid; δ_(H) (250 MHz, CDCl₃) 8.49 (1H, d, J 4.5, pyridineAr), 7.60 (1H, td, J 8.0, 2.0, pyridine Ar), 7.22-7.12 (2H, m, 2×pyridine Ar), 5.85 (1H, br, NH), 5.75 (1H, s, pyrimidine Ar), 4.56 (2H,d, J 5.0, NHCH₂), 3.68-3.60 (8H, m, 4× morpholine CH₂).

Using an analogous method the following further compounds (16) wereprepared:

2-chloro-4-(morpholin-4-yl)-6-(pyridin-3-ylmethylamino)pyrimidine (L2)

δ_(H) (250 MHz, CDCl₃) 8.51 (1H, d, J 2.0, pyridine Ar), 8.46 (1H, dd, J5.0, 1.5, pyridine Ar), 7.57 (1H, dd, J 8.0, 2.0, pyridine Ar),7.23-7.18 (1H, m, pyridine Ar), 5.68 (1H, s, pyrimidine Ar), 5.03 (1H,br, NH), 4.49 (2H, d, J 6.0, NHCH₂), 3.68-3.60 (8H, m, 4× morpholineCH₂).

2-chloro-4-(morpholin-4-yl)-6-(pyridin-4-ylmethylamino)pyrimidine (M2)

δ_(H) (250 MHz, CDCl₃) 8.52 (2H, d, J 6.0, 2× pyridine Ar), 7.33 (2H, d,J 6.0, 2× pyridine Ar), 5.72 (1H, s, pyrimidine Ar), 5.36 (1H, br, NH),4.57 (2H, d, J 6.0, NHCH₂), 3.65-3.55 (8H, m, 4× morpholine CH₂).

2-chloro-4-(morpholin-4-yl)-6-[(2-(pyridin-2-yl)ethylamino]pyrimidine(N2)

δ_(H) (250 MHz, CDCl₃) 8.48 (1H, dt, J 5.0, 1.5 pyridine Ar), 7.55 (1H,td, J 7.5, 2.0, pyridine Ar), 7.12-7.07 (2H, m, 2× pyridine Ar), 5.64(1H, s, pyrimidine Ar), 5.39 (1H, br, NH), 3.65-3.62 (10H, m, 4×morpholine CH₂, NHCH₂), 2.98 (2H, t, J 6.5, ArCH₂).

2-chloro-4-(morpholin-4-yl)-6-[(2-(pyridin-3-yl)ethylamino]pyrimidine(O2)

δ_(H) (250 MHz, CDCl₃) 8.44-8.39 (2H, m, 2× pyridine Ar), 7.45 (1H, dt,J 8.0, 2.0, pyridine Ar), 7.20-7.16 (1H, m, pyridine Ar), 5.62 (1H, s,pyrimidine Ar), 4.73 (1H, br, NH), 3.66 (8H, br s, 4× morpholine CH₂),3.52 (2H, br q J 6.5, NHCH₂), 2.83 (2H, t J 7.0, ArCH₂).

2-chloro-4-(morpholin-4-yl)-6-[(2-(pyridin-4-yl)ethylamino]pyrimidine(P2)

δ_(H) (250 MHz, CDCl₃) 8.58 (2H, d, J 6.0, 2× pyridine Ar), 7.24 (2H, d,J 6.0, 2× pyridine Ar), 5.74 (1H, s, pyrimidine Ar), 4.88 (1H, br, NH),3.80-3.63 (10H, m, 4× morpholine CH₂, NHCH₂), 2.98 (2H, t, J 7.0,ArCH₂).

2-chloro-4-(morpholin-4-yl)-6-[2-(morpholin-4-yl)ethylamino]pyrimidine(Q2)

δ_(H) (250 MHz, CDCl₃) 5.67 (1H, s, pyrimidine Ar), 5.22 (1H, br, NH),3.70-3.62 (12H, m, 6× morpholine CH₂), 3.30 (2H, br, NHCH₂), 2.50 (2H,t, J 6.0, NCH₂), 2.40 (4H, t, J 4.5, 1× morpholine CH₂).

2-chloro-4-(morpholin-4-yl)-6-(pyridin-2-ylmethyloxy)pyrimidine (R2)

δ_(H) (250 MHz, CDCl₃) 8.51 (1H, d, J 4.5, 1× pyridine Ar), 7.63 (1H,td, J 8.0, 2.0, 1× pyridine Ar), 7.31 (1H, d, J 8.0, 1× pyridine Ar),7.16 (1H, dd, J 7.0, 5.5, 1× pyridine Ar), 6.08 (1H, s, pyrimidine Ar),5.40 (2H, s, OCH₂), 3.68-3.59 (8H, m, 4× morpholine CH₂).

REFERENCE EXAMPLE 5 Preparation of Intermediates (23) in Scheme 6 Ethyl2-(3-benzyloxyphenyl)-4-hydroxypyrimidine carboxylate (H3)

To a solution of the malonate derivative (24) 1.5 g, 6.95 mmol) and theamidine S (1.1 eq, 7.65 mmol, 1.73 g) in ethanol (20 ml) was addedsodium ethoxide (1.1 eq, 7.65 mmol, 520 mg) and the mixture stirred atroom temperature for 4 h. After this time, the solid product wasfiltered off and allowed to dry in air, affording 1.56 g (64%) as a paleyellow solid; δ_(H) (250 MHz, DMSO-d₆) 8.54 (1H, br, pyrimidine Ar),7.96-7.90 (2H, br, 2×Ar), 7.48-7.32 (6H, br, 6×Ar), 7.06 (1H, br d, J7.0, Ar), 5.17 (2H, br, s, OCH₂), 4.17 (2H, br q, J 6.5, CO₂CH₂), 1.27(3H, br, t, J 6.5, CO₂CH₂CH₃).

REFERENCE EXAMPLE 6 Preparation of Intermediates (22) in Scheme 6 Ethyl2-(3-benzyloxyphenyl)-4-(morpholin-4-yl)pyrimidine carboxylate (I3)

A solution of compound H3 (225 mg, 0.64 mmol) in POCl₃ (2 ml) containingN, N-dimethylaniline (1.1 eq, 0.71 mmol, 0.09 ml) was stirred at 110° C.for 18 h. The POCl₃ was removed in vacuo and the residue azeotroped withtoluene (5 ml), re-dissolved in CHCl₃ (5 ml) and poured into ice. Theorganic layer was separated, washed with water, dried (MgSO₄) andconcentrated in vacuo. The crude product was dissolved in dioxane (2 ml)and treated with DIPEA (2 eq, 1.28 mmol, 0.22 ml) and morpholine (5 eq,3.21 mmol, 0.28 ml) and heated at 80° C. for 4 h. The dioxane wasevaporated in vacuo, and the residue partitioned between H₂O (5 ml) andCHCl₃ (5 ml). The organic layer was separated and the aqueous layerfurther extracted with CHCl₃ (2×2 ml). The combined extracts were dried(Na₂SO₄) and concentrated in vacuo. Purification by columnchromatography (hexane-EtOAc, 3:1) gave the product (196 mg, 73% for twosteps) as a colourless solid; δ_(H) (250 MHz, CDCl₃) 8.79 (1H, s,pyrimidine Ar), 7.96-7.92 (2H, m, 2×Ar), 7.42-7.23 (6H, m, 6× Ar),7.06-7.02 (1H, m, Ar), 5.09 (2H, s, OCH₂), 4.30 (2H, q, J 7.0, CO₂CH₂),3.76-3.72 (4H, m, 2× morpholine CH₂), 3.65-3.60 (4H, m, 2× morpholineCH₂), 1.32 (3H, t, J 7.0, CO₂CH₂CH₃).

REFERENCE EXAMPLE 7 Preparation of Intermediates (21) in Scheme 62-(3-benzyloxyphenyl)-4-(morpholin-4-yl)pyrimidine carboxylic acid (J3)

A solution of compound I3 (94 mg) in THF-MeOH-water (5:2:2, 1.5 ml) wastreated with lithium hydroxide (5 eq, 1.79 mmol, 75 mg) and stirred at100° C. for 1.5 h. After this time it was cooled and carefully acidifiedwith 2M HCl, causing precipitation of the product (51 mg) as a yellowsolid; δ_(H) (250 MHz, DMSO-d₆) 8.63 (1H, s, pyrimidine Ar), 7.97-7.93(2H, s, 2×Ar), 7.55-7.30 (6H, m, 6× Ar), 7.19-7.15 (1H, m, Ar), 5.20(2H, s, OCH₂), 3.68-3.65 (8H, m, 4× morpholine CH₂).

REFERENCE EXAMPLE 8 Preparation of Intermediates (27) in Scheme 72-chloro-4-(morpholin-4-yl)-5-nitropyrimidine (K3)

A solution of the dichloropyrimidine (1.00 g, 5.16 mmol) in acetone (10ml) at 0° C. containing Na₂CO₃ (1.0 eq, 5.16 mmol, 546 mg) was treateddropwise with a solution of morpholine (1.0 eq, 5.16 mmol, 0.45 ml) inacetone (3 ml) and stirred for 1 h at 0° C. Tlc (DCM-hexane, 4:2) showedcompletion of the reaction to give two products. The acetone was removedin vacuo and the residue partitioned between water and EtOAc, theorganic layer dried (MgSO₄) and evaporated in vacuo. Columnchromatography (DCM-EtOAC, 9:1) gave the product (560 mg, 45%) as a paleyellow solid, together with 260 mg (17%) of the disubstituted productalso as a yellow solid.

-   K3: δ_(H) (250 MHz, CDCl₃) 8.68 (1H, s, pyrimidine Ar), 3.75-3.71    (4H, m, 2× morpholine CH₂), 3.57-3.53 (4H, m, 2× morpholine CH₂).

REFERENCE EXAMPLE 9 Preparation of Intermediate of Formula (26) inScheme 7 2-(3-methoxyphenyl)-4-(morpholin-4-yl)-5-nitropyrimidine (L3)

A solution of compound K3(100 mg, 0.41 mmol) in DME-H₂O-EtOH (7:3:2, 2.5ml) in a sealable tube was treated with PdCl₂(dppf) (5 mol %, 17 mg),3-methoxyphenylboronic acid (2.2 eq, 0.90 mmol, 136 mg) and Na₂CO₃ (2.0eq, 0.82 mmol, 88 mg), sealed and heated at 150° C. in a microwaveapparatus for 10 minutes. The solvents were then removed in vacuo andthe residue was partitioned between water and CHCl₃, the organic phaseseparated and dried (MgSO₄) and concentrated in vacuo. Columnchromatography (DMC-EtOAc, 95:5) gave the product (50 mg, 39%) as ayellow solid; δ_(H) (250 MHz, CDCl₃) 9.07 (1H, s, pyrimidine Ar),8.04-8.00 (2H, m, 2×Ar), 7.44 (1H, t, J 8.0, Ar), 7.13 (1H, ddd, J 8.0,2.5, 1.0, Ar), 3.94 (3H, s, OCH₃), 3.90-3.87 (4H, m, 2× morpholine CH₂),3.77-3.74 (4H, m, 2× morpholine CH₂).

REFERENCE EXAMPLE 10 Preparation of Intermediate (25) in Scheme 75-amino-2-(3-methoxyphenyl)-4-(morpholin-4-yl)pyrimidine (M3)

A solution of the nitro compound L3 (31 mg, 0.099 mmol) in EtOH-EtOAc(1:1, 2 ml) containing 10% Pd on carbon (5 mg) was stirred under aballoon of hydrogen gas for 1.5 hours. tlc (DCM-EtOAc, 9:1) then showedcompletion of the reaction. The mixture was diluted with EtOAc andfiltered through a short pad of celite and the solvents evaporated invacuo to give the amine (25 mg, 89%) as an oil; δ_(H) (250 MHz, CDCl₃)8.03 (1H, s, pyrimidine Ar), 7.87-7.83 (2H, m, Ar), 7.28 (1H, t, J 8.0,Ar), 6.89 (1H, ddd, J 8.0, 2.5, 1.0 Ar), 3.83 (3H, s, OCH₃), 3.80-3.75(4H, m, 2 x morpholine CH₂), 3.64 (2H, br, NH₂), 3.47-3.43 (4H, m, 2×morpholine CH₂).

EXAMPLE 1 Preparation of Compounds of Formulae (Ib) and (Ic) in Scheme 5

A solution of compound F2 (50 mg, 0.15 mmol), Bedford palladacycle(prepared as described in Organometallics 2003, 22, 987; 5 mol %, 5 mg)and indole-4-boronic acid (2.2 eq, 0.34 mmol, 55 mg) in DME (1 ml) in amicrowave tube was stirred for 5 minutes. Aqueous sodium carbonate (2M,2.2 eq, 0.34 mmol, 0.17 ml) was added and the mixture stirred withmicrowave heating at 150° C. for 30 minutes. After this time it wasallowed to cool to room temperature and passed through a short silicacolumn, eluting with CH₂Cl₂-MeOH, 9:1. After concentration of thecombined eluents in vacuo, the residue was purified by columnchromatography (CHCl3-MeOH, 9:1) to give the product (25 mg, 40%) as apale brown solid.

δ_(H) (500 MHz, CD₃OD) 8.44 (1H, d, J 4.0, pyridine Ar), 7.71 (1H, td, J7.7, 1.8, pyridine Ar), 7.47 (1H, d, J 8.1, indole Ar), 7.37 (1H, d, J7.1, pyridine Ar), 7.33 (1H, d, J 7.8, indole Ar), 7.31 (1H, d, J 3.2,indole Ar), 7.23 (1H, dd, J 7.0, 5.5, pyridine Ar), 7.17 (1H, t, J 7.7,indole Ar), 6.79 (1H, br, indole Ar), 6.40 (1H, s, pyrimidine Ar), 3.80(2H, t, J 6.9, NHCH₂), 3.76-3.74 (4H, m, 2× morpholine CH₂), 3.65-3.63(4H, m, 2× morpholine CH₂), 3.14 (2H, t, J 6.9, ArCH₂).

Using an analogous method and either indole 4-boronic acid or indole6-boronic acid, the following further compounds of formulae (Ib) and(Ic) were prepared:

δ_(H) (500 MHz, CDCl₃) 8.58 (1H, d, J 4.4, pyridine Ar), 8.46 (1H, s,br, NH), 7.62 (1H, td, J 7.6, 1.8, pyridine Ar), 7.54 (1H, d, J 6.8,pyridine Ar), 7.41 (1H, d, J 8.1, indole Ar), 7.24-7.28 (2H, m, 2×indole Ar), 7.18 (1H, d, J 7.8, indole Ar), 7.16 (1H, dd, J 7.5, 4.9,pyridine Ar), 7.07 (1H, t, J 2.2, indole Ar), 6.22 (1H, s, pyrimidineAr), 5.23 (1H, t, J 5.5, NH), 3.89-3.87 (4H, m, 2× morpholine CH₂),3.84-3.81 (2H, m, NHCH₂), 3.80-3.78 (4H, m, 2× morpholine CH₂), 3.12(2H, t, J 6.6, ArCH₂).

δ_(H) (500 MHz, DMSO-d₆) 11.20 (1H, br, NH), 8.47 (1H, d, J 2.0,pyridine Ar), 8.40 (1H, dd, J 4.7, pyridine Ar), 7.67 (1H, dt, J 7.9, 2,pyridine Ar), 7.54 (1H, d, J 7.9 indole Ar), 7.48 (1H, d, J 7.9, indoleAr), 7.40 (1H, t, J 2.8, indole Ar), 7.31 (1H, dd, J 7.6, 4.7, pyridineAr), 7.15 (1H, t, J 7.6, indole Ar), 7.01 (1H, br, indole Ar), 6.49 (1H,s, br, pyrimidine Ar), 3.70-3.68 (4H, m, 2× morpholine CH₂), 3.59-3.57(6H, m, 2× morpholine CH₂, NHCH₂), 2.92 (2H, t, J 7.3, ArCH₂).

δ_(H) (500 MHz, CD₃OD) 8.43 (1H, d, J 1.8, pyridine Ar), 8.36 (1H, dd, J4.7, 1.8, pyridine Ar), 7.75 (1H, dt, J 8.0, 1.9, pyridine Ar),7.46-7.44 (2H, m, 2× indole Ar), 7.36 (1H, dd, J 7.8, 4.7, pyridine Ar),7.30 (1H, d, J 3.2, indole Ar), 7.16 (1H, t, J 7.7, indole Ar), 6.89(1H, dd, J 3.1, 0.6, indole Ar), 6.28 (1H, s, pyrimidine Ar), 3.82-3.80(4H, m, 2× morpholine CH₂), 3.77-3.75 (4H, m, 2× morpholine CH₂),3.71-3.68 (2H, m, NHCH₂), 2.99 (2H, t, J 6.9, ArCH₂).

δ_(H) (250 MHz, CDCl₃) 8.52 (2H, dd, J 4.4, 1.6, 2× pyridine Ar), 8.31(1H, s, br, NH), 7.55 (1H, d, J 7.3, indole Ar), 7.46 (1H, d, J 8.2,indole Ar), 7.30-7.26 (1H, m, indole Ar), 7.20 (2H, dd, J 4.4, 1.6, 2×pyridine Ar), 7.03 (1H, br, indole Ar), 6.42 (1H, s, indole Ar), 5.31(1H, s, pyrimidine Ar), 3.81-3.79 (4H, m, 2× morpholine CH₂), 3.77 (2H,td, J 7.0, 6.6, NHCH₂), 3.66-3.64 (4H, m, 2× morpholine CH₂), 2.98 (2H,t, J 7.0, ArCH₂).

δ_(H) (500 MHz, CD₃OD) 8.57 (2H, d, J 5.7, 2× pyridine Ar), 7.44 (2H, d,J 7.7, 2× indole Ar), 7.31 (2H, d, J 5.6, 2× pyridine Ar), 7.29 (1H, d,J 3.1, indole Ar), 7.15 (1H, t, J 7.7, indole Ar), 6.89 (1H, d, J 3.1,indole Ar), 6.27 (1H, s, pyrimidine Ar), 3.81-3.79 (4H, m, 2× morpholineCH₂), 3.76-3.74 (4H, m, 2× morpholine CH₂), 3.69 (2H, t, J 6.9, NHCH₂),2.98 (2H, t, J 6.9, ArCH₂).

δ_(H) (500 MHz, CD₃OD) 8.53 (1H, d, J 4.4, pyridine Ar), 7.86 (1H, td, J7.8, 1.7, pyridine Ar), 7.58-7.55 (2H, m, 1× pyridine Ar, 1× indole Ar),7.50 (1H, d, J 8.0, indole Ar), 7.36 (1H, dd, J 7.2, 5.2, pyridine Ar),7.34 (1H, d, J 3.2, indole Ar), 7.19 (1H, t, J 8.0, indole Ar), 6.96(1H, d, J 3.2, indole Ar), 6.68 (1H, s, pyrimidine Ar), 5.52 (2H, s,OCH₂), 3.82-3.80 (4H, m, 2× morpholine CH₂), 3.73-3.71 (4H, m, 2×morpholine CH₂).

δ_(H) (500 MHz, CD₃OD) 8.49 (1H, d, J 4.2, pyridine Ar), 7.79 (1H, td, J7.7, 1.7, pyridine Ar), 7.59 (1H, d, J 7.8, indole Ar), 7.48-7.47 (2H,d, J 7.8, 1× indole Ar, 1× pyridine Ar), 7.31-7.29 (2H, m, 1× indole Ar,1× pyridine Ar), 7.16 (1H, t, J 7.7, indole Ar), 6.79 (1H, dd, J 3.2,0.8, indole Ar), 6.73 (1H, s, pyrimidine Ar), 5.51 (2H, s, OCH₂), 3.67(4H, m, 2× morpholine CH₂), 3.58-3.56 (4H, m, 2× morpholine CH₂).

δ_(H) (250 MHz, CDCl₃) 9.78 (1H, br, NH), 8.49 (1H, d, J 4.5, pyridineAr), 8.19 (1H, s, indole Ar), 7.61 (1H, d, J 8.1, indole Ar), 7.58 (1H,d, J 8.1, indole Ar), 7.52 (1H, td, J 7.6, 1.5, pyridine Ar), 7.15 (1H,br, indole Ar), 7.12 (1H, d, J 7.7, pyridine Ar), 7.07 (1H, dd, J 7.1,4.5, pyridine Ar), 6.47 (1H, s, pyrimidine Ar), 6.29 (1H, br, indoleAr), 3.86-3.83 (2H, m, NHCH₂), 3.76-3.74 (4H, m, 2× morpholine CH₂),3.62-3.60 (4H, m, 2× morpholine CH₂), 3.09 (2H, t, J 7.0, ArCH₂).

δ_(H) (500 MHz, CD₃OD) 8.45 (1H, d, J 4.5, pyridine Ar), 8.05 (1H, s,indole Ar), 7.70 (1H, td, J 7.8, 1.8, pyridine Ar), 7.61 (1H, dd, J 8.5,1.2, indole Ar), 7.57 (1H, d, J 8.5 indole Ar), 7.29 (1H, d, J 7.8,pyridine Ar), 7.27 (1H, d, J 3.1, indole Ar), 7.22 (1H, dd, J 6.6, 4.5,pyridine Ar), 6.46 (1H, dd, J 3.1, 0.6, indole Ar), 6.25 (1H, s,pyridine Ar), 3.84-3.82 (4H, m, 2× morpholine CH₂), 3.78-3.74 (6H, m, 2×morpholine CH₂, NHCH₂), 3.09 (2H, t, J 6.9, ArCH₂).

δ_(H) (500 MHz, CDCl₃) 9.22 (1H, br s, NH), 8.49 (1H, s, pyridine Ar),8.44 (1H, dd, J 4.8, 1.6, pyridine Ar), 8.17 (1H, s, indole Ar), 7.65(1H, d, J 8.3, indole Ar), 7.61 (1H, d, J 8.3, indole Ar), 7.47 (1H, d,J 7.5, pyridine Ar), 7.20 (1H, t, J 2.9, indole Ar), 7.16 (1H, dd, J7.5, 4.8, pyridine Ar), 6.52 (1H, br m, indole Ar), 6.35 (1H, s,pyrimidine Ar), 3.79-3.77 (4H, m, 2× morpholine CH₂), 3.64-3.60 (6H, m,2× morpholine CH₂, NHCH₂), 2.87 (2H, t, J 6.9, ArCH₂).

δ_(H) (500 MHz, CD₃OD) 8.40 (1H, S, pyridine Ar), 8.35 (1H, d, J 3.9,pyridine Ar), 8.04 (1H, s, indole Ar), 7.68 (1H, d, J 7.8, pyridine Ar),7.60 (1H, dd, J 8.3, 1.4, indole Ar) 7.57 (1H, d, J 8.3, indole Ar),7.32 (1H, dd, J 7.7, 4.9, pyridine Ar), 7.27 (1H, d, J 3.1, indole Ar),6.46 (1H, dd, J 3.1, 0.7, indole Ar), 6.24 (1H, s, pyrimidine Ar),3.84-3.82 (4H, m, 2× morpholine CH₂), 3.78-3.76 (4H, m 2× morpholineCH₂), 3.66 (2H, t, J 7.0, NHCH₂), 2.96 (2H, t, J 7.0, ArCH₂).

δ_(H) (500 MHz, CD₃OD) 8.44 (2H, d, J 6.0, 2× pyridine Ar), 7.96 (1H, s,indole Ar), 7.64 (1H, d, J 8.5, indole Ar), 7.54 (1H, d, J 8.5, indoleAr), 7.38-7.37 (3H, m, 2× pyridine Ar, 1× indole Ar), 6.52 (1H, s,pyrimidine Ar), 6.51 (1H, dd, J 3.2, 0.7, indole Ar), 3.80-3.74 (10H, 4×morpholine CH₂, NHCH₂), 3.04 (2H, t, J 6.9, ArCH₂).

δ_(H) (500 MHz, CD₃OD) 8.43 (2H, dd, J 4.5, 1.5, 2× pyridine Ar), 8.07(1H, br s, indole Ar), 7.60 (1H, dd, J 8.4, 1.5, indole Ar), 7.56 (1H,d, J 8.4, indole Ar), 7.34 (2H, dd, J 4.5, 1.5, 2× pyridine Ar), 7.31(1H, d, J 3.1, indole Ar), 6.46 (1H, d, J 3.1, indole Ar), 6.28 (1H, s,2× pyridine Ar), 3.72 (2H, t, J 6.9, NHCH₂) 3.84-3.82 (4H, m, 2×morpholine CH₂), 3.78-3.76 (4H, m, 2× morpholine CH₂) 3.00 (2H, t, J6.9, ArCH₂).

δ_(H) (500 MHz, CD₃OD) 8.53 (1H, d, J 5.5, pyridine Ar), 8.17 (1H, s,indole Ar), 7.86 (1H, td, J 7.7, 1.8, pyridine Ar), 7.72 (1H, dd, J 8.3,1.6, indole Ar), 7.60 (1H, d, J 8.4, indole Ar), 7.56 (1H, d, J 7.5,pyridine Ar), 7.36 (1H, dd, J 7.5, 5.5, pyridine Ar), 7.33 (1H, d, J3.3, indole Ar), 6.69 (1H, s, pyrimidine Ar), 6.48 (1H, dd, J 3.1,indole Ar), 5.51 (2H, s, OCH₂), 3.84-3.71 (4H, m, 2× morpholine CH₂),3.32-3.32 (4H, m, 2 x morpholine CH₂).

δ_(H) (500 MHz CDCl₃) 8.59 (1H, d, J 4.8, pyridine Ar), 8.39 (1H, br,NH), 8.68 (1H, s, indole Ar), 7.70-7.67 (3H, m, 2× indole Ar, 1×pyridine Ar), 7.59 (1H, d, J 7.9, pyridine Ar), 7.30 (1H, t, J 2.8,indole Ar), 7.19 (1H, dd, J 6.9, 5.4, pyridine Ar), 6.67 (1H, s,pyrimidine Ar), 6.58 (1H, br, indole Ar), 5.64 (2H, s, OCH₂), 3.79-3.77(4H, m, 2× morpholine CH₂), 3.69-3.67 (4H, m, 2× morpholine CH₂).

EXAMPLE 2 Preparation of Compounds of Formula (Ia) in Scheme 72-(3-methoxyphenyl)-4-(morpholin-4-yl)-5-[(pyridin-4-yl)carbonylamino]pyrimidine(N3)

A solution of the amine M3 (25 mg, 0.087 mmol) in CHCl₃ (1 ml) at roomtemperature was treated with diisopropylethylamine (2.5 eq, 0.21 mmol,0.03 ml) and the acid chloride (2.2 eq, 0.196 mmol, 34 mg) and stirredat room temp for 1 h. tlc (DCM-EtOAc, 9:1) showed incomplete reaction.Further base (0.03 ml) and acid chloride (34 mg) were added and thereaction stirred at room temperature for 18 h. tlc then showed completeconversion. A standard aqueous work up and column chromatography (sameeluent) gave the product (16 mg, 47%) as a colourless solid; δ_(H) (250MHz, CDCl₃) 9.03 (1H, s, pyrimidine Ar), 8.79-8.61 (3H, m, 2× pyridineAr, NH), 7.94-7.89 (2H, m, Ar), 7.76 (2H, d, J 5.0, pyridine Ar), 7.34(1H, t, J 8.0, Ar), 6.99 (1H, ddd, J 8.0, 2.5, 1.0, Ar), 3.85 (3H, s,OCH₃), 3.81-3.72 (4H, m, 2× morpholine CH₂), 3.57-3.53 (4H, m, 2×morpholine CH₂).

Using an analogous method, the following further compounds of formula(Ia) were prepared:

2-(3-methoxyphenyl)-4-(morpholin-4-yl)-5-[(pyridin-3-yl)carbonylamino]pyrimidine(O3)

δ_(H) (250 MHz, CDCl₃) 9.17 (1H, br, NH), 9.05 (1H, d, J 2.0, pyrimidineAr), 8.77 (1H, dd, J 5.0, 1.5, pyridine Ar), 8.21 (1H, dt, J 8.0, 2.0,pyridine Ar), 7.96-7.87 (3H, m, 2× pyridine Ar, 1×Ar), 7.44 (1H, dd, J8.0, 5.5, Ar), 7.32 (1H, t, J 8.0, Ar), 6.95 (1H, ddd, J 8.0, 2.5, 1.0,Ar), 3.84 (3H, s, OCH₃), 3.83-3.79 (4H, m, 2× morpholine CH₂), 3.45-3.41(4H, m, 2× morpholine CH₂).

2-(3-methoxyphenyl)-4-(morpholin-4-yl)-5-[(pyridin-3-yl)carbonylamino]pyrimidine(P3)

δ_(H) (250 MHz, CDCl₃) 9.96 (1H, br, NH), 9.40 (1H, s, pyrimidine Ar),8.58 (1H, dq, J 4.5, 1.0, pyridine Ar), 8.24 (1H, dt, J 8.0, 1.0,pyridine Ar), 7.97-7.85 (3H, m, 2× pyridine Ar, 1×Ar), 7.47 1H, ddd, J8.0, 5.0, 1.0, Ar), 7.31 (1H, t, J 8.0, Ar), 6.94 (1H, ddd, J 8.0, 2.5,1.0, Ar), 3.90-3.87 (4H, 2× morpholine CH₂), 3.85 (3H, s, OCH₃),3.46-3.43 (4H, m, 2× morpholine CH₂).

EXAMPLE 3 Biological Testing

Compounds of the invention, prepared as described in the precedingExamples, were submitted to the following series of biological assays:

(i) PI3K Biochemical Screening

Compound inhibition of PI3K was determined in a radiometric assay usingpurified, recombinant enzyme and ATP at a concentration of 1 uM. Allcompounds were serially diluted in 100% DMSO. The kinase reaction wasincubated for 1 hour at room temperature, and the reaction wasterminated by the addition of PBS. IC₅₀ values were subsequentlydetermined using sigmoidal dose-response curve fit (variable slope). Allof the compounds tested had an IC₅₀ against PI3K of 50 μM or less.Typically the IC₅₀ against PI3K was 5-500 nM.

(ii) Cellular Proliferation Inhibition

Cells were seeded at optimal density in a 96 well plate and incubatedfor 4 days in the presence of test compound. Alamar Blue™ wassubsequently added to the assay medium, and cells were incubated for 6hours before reading at 544 nm excitation, 590 nm emission. EC₅₀ valueswere calculated using a sigmoidal dose response curve fit. All thecompounds tested had an EC₅₀s of 50 uM or less in the range of celllines utilized.

EXAMPLE 4 Tablet Composition

Tablets, each weighing 0.15 g and containing 25 mg of a compound of theinvention were manufactured as follows:

Composition for 10,000 tablets Compound of the invention (250 g) Lactose(800 g) Corn starch (415 g) Talc powder (30 g) Magnesium stearate (5 g)

The compound of the invention, lactose and half of the corn starch weremixed. The mixture was then forced through a sieve 0.5 mm mesh size.Corn starch (10 g) is suspended in warm water (90 ml). The resultingpaste was used to granulate the powder. The granulate was dried andbroken up into small fragments on a sieve of 1.4 mm mesh size. Theremaining quantity of starch, talc and magnesium was added, carefullymixed and processed into tablets.

EXAMPLE 5 Injectable Formulation

Compound of the invention 200 mg Hydrochloric Acid Solution 0.1M or 4.0to 7.0 Sodium Hydroxide Solution 0.1M q.s. to pH Sterile water q.s. to10 ml

The compound of the invention was dissolved in most of the water (35°40° C.) and the pH adjusted to between 4.0 and 7.0 with the hydrochloricacid or the sodium hydroxide as appropriate. The batch was then made upto volume with water and filtered through a sterile micropore filterinto a sterile 10 ml amber glass vial (type 1) and sealed with sterileclosures and overseals.

EXAMPLE 6 Intramuscular Injection

Compound of the invention 200 mg Benzyl Alcohol 0.10 g Glycofurol 751.45 g Water for injection q.s to 3.00 ml

The compound of the invention was dissolved in the glycofurol. Thebenzyl alcohol was then added and dissolved, and water added to 3 ml.The mixture was then filtered through a sterile micropore filter andsealed in sterile 3 ml glass vials (type 1).

EXAMPLE 7 Syrup Formulation

Compound of invention 250 mg Sorbitol Solution 1.50 g Glycerol 2.00 gSodium benzoate 0.005 g Flavour 0.0125 ml Purified Water q.s. to 5.00 ml

The compound of the invention was dissolved in a mixture of the glyceroland most of the purified water. An aqueous solution of the sodiumbenzoate was then added to the solution, followed by addition of thesorbital solution and finally the flavour. The volume was made up withpurified water and mixed well.

1. A compound which is a pyrimidine of formula (I):

wherein —XR³ is bonded at ring position 2 and —YR⁴ is bonded at ringposition 5 or 6, or —YR⁴ is bonded at ring position 2 and —XR³ is bondedat ring position 6; R¹ and R² form, together with the N atom to whichthey are attached, a morpholine ring which is unsubstituted orsubstituted; X is selected from a direct bond, —O—, —CR′R″— and —NR′—wherein R′ and R″ are each, independently, H or C₁-C₆ alkyl; R³ is anindole group which is unsubstituted or substituted; and either: (a) Y isselected from —O—(CH₂)_(n)—, —NH—(CH₂)_(n)—, —NHC(O)—(CH₂)_(n)— and—C(O)NH—(CH₂)_(n)— wherein n is 0 or an integer of 1 to 3, and R⁴ isselected from an unsaturated 5- to 12-membered carbocyclic orheterocyclic group which is unsubstituted or substituted, and a group—NR⁵R⁶ wherein R⁵ and R⁶, which are the same or different, are eachindependently selected from H, C₁-C₆ alkyl which is unsubstituted orsubstituted, C₃-C₁₀ cycloalkyl which is unsubstituted or substituted,—C(O)R, —C(O)N(R)₂ and —S(O)_(m)R wherein R and m are as defined above,or R⁵ and R⁶ together form, with the nitrogen atom to which they areattached, a saturated 5-, 6- or 7-membered N-containing heterocyclicgroup which is unsubstituted or substituted; (b) Y is a direct bond andR⁴ is selected from an unsaturated 5- to 12-membered carbocyclic orheterocyclic group which is unsubstituted or substituted, and a group—NR⁵R⁶ wherein R⁵ and R⁶, which are the same or different, are eachindependently selected from H, C₁-C₆ alkyl which is unsubstituted orsubstituted, C₃-C₁₀ cycloalkyl which is unsubstituted or substituted,—C(O)R, —C(O)N(R)₂ and —S(O)_(m)R wherein R and m are as defined above;or a pharmaceutically acceptable salt thereof.
 2. A compound accordingto claim 1 wherein the pyrimidine is of formula (Ia):

in which R¹, R², R³, R⁵, Y and X are as defined in claim
 1. 3. Acompound according to claim 1 wherein the pyrimidine is of formula (Ib):

in which R¹, R², R³, R⁴, Y and X are as defined in claim
 1. 4. Acompound according to claim 1 wherein the pyrimidine is of formula (Ic):

in which R¹, R², R³, R⁴, Y and X are as defined in claim
 1. 5. Acompound according to claim 1 wherein —X is a direct bond.
 6. A compoundaccording to claim 1 which is selected from:6-(indol-4-yl)-4-(morpholin-4-yl)-2-[(2-(pyridin-2-yl)ethylamino]pyrimidine;2-(indol-4-yl)-4-(morpholin-4-yl)-6-[(2-(pyridin-2-yl)ethylamino]pyrimidine;6-(indol-4-yl)-4-(morpholin-4-yl)-2-[(2-(pyridin-3-yl)ethylamino]pyrimidine;2-(indol-4-yl)-4-(morpholin-4-yl)-6-[(2-(pyridin-3-yl)ethylamino]pyrimidine;6-(indol-4-yl)-4-(morpholin-4-yl)-2-[(2-(pyridin-4-yl)ethylamino]pyrimidine;2-(indol-4-yl)-4-(morpholin-4-yl)-6-[(2-(pyridin-4-yl)ethylamino]pyrimidine;2-(indol-4-yl)-4-(morpholin-4-yl)-6-(pyridin-2-ylmethyloxy)pyrimidine;6-(indol-4-yl)-4-(morpholin-4-yl)-2-(pyridin-2-ylmethyloxy)pyrimidine;6-(indol-6-yl)-4-(morpholin-4-yl)-2-[(2-(pyridin-2-yl)ethylamino]pyrimidine;2-(indol-6-yl)-4-(morpholin-4-yl)-6-[(2-(pyridin-2-yl)ethylamino]pyrimidine;6-(indol-6-yl)-4-(morpholin-4-yl)-2-[(2-(pyridin-3-yl)ethylamino]pyrimidine;2-(indol-6-yI)-4-(morpholin-4-yl)-6-[(2-(pyridin-3-yl)ethylamino]pyrimidine;6-(indol-6-yl)-4-(morpholin-4-yl)-2-[(2-(pyridin-4-yl)ethylamino]pyrimidine;2-(indol-6-yl)-4-(morpholin-4-yl)-6-[(2-(pyridin-4-yl)ethylamino]pyrimidine;2-(indol-6-yl)-4-(morpholin-4-yl)-6-(pyridin-2-ylmethyloxy)pyrimidine;6-(indol-6-yl)-4-(morpholin-4-yl)-2-(pyridin-2-ylmethyloxy)pyrimidine;and the pharmaceutically acceptable salts thereof.
 7. A pharmaceuticalcomposition which comprises a pharmaceutically acceptable carrier ordiluent and, as an active ingredient, a compound as defined in claim 1.